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Thesis for doctoral degree (Ph.D.) 2019

Physical function, physical activity and quality of life in systemic sclerosis

Henrik Pettersson

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From THE DEPARTMENT OF MEDICINE, SOLNA Karolinska Institutet, Stockholm, Sweden

PHYSICAL FUNCTION, PHYSICAL ACTIVITY AND QUALITY OF LIFE

IN SYSTEMIC SCLEROSIS

Henrik Pettersson

Stockholm 2019

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All previously published papers were reproduced with permission from the publisher.

Published by Karolinska Institutet.

Printed by Arkitektkopia AB, 2019

© Henrik Pettersson, 2019 ISBN 978-91-7831-420-1

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Principal Supervisor:

RPT. Ph.D., Associate Professor Carina Boström

Karolinska Institutet

Department of Neurobiology, Care Sciences and Society Division of Physiotherapy Co-supervisor(s):

M.D. Ph.D., Annica Nordin Karolinska Institutet

Department of Medicine, Solna Division of Rheumatology RPT. Ph.D., Associate Professor Helene Alexanderson

Karolinska Institutet

Department of Neurobiology, Care Sciences and Society Division of Physiotherapy M.D. Ph.D., Professor Elisabet Svenungsson Karolinska Institutet

Department of Medicine, Solna Division of Rheumatology

Opponent:

RPT. Ph.D., Professor Ann Bremander

University of Southern Denmark, Odense Department of Regional Health Research, Denmark

Examination Board:

M.D. Ph.D., Associate Professor Dirk Marcus Wuttge

Lund University

Department of Clinical Sciences, Section of Rheumatology,

and Skåne University Hospital-Lund RPT. Ph.D., Professor

Kaisa Mannerkorpi University of Gothenburg

Department of Health and Rehabilitation Institute of Neuroscience and Physiology RPT. Ph.D., Professor

Anne Marit Mengshoel University of Oslo

Institute of Health and Society Department of Interdisciplinary Health Sciences, Institute of Health and Society, Norway

Physical function, physical activity and quality of life in systemic sclerosis

THESIS FOR DOCTORAL DEGREE (Ph.D.)

By

Henrik Pettersson

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To all patients with SSc with the hope that this Thesis will spread some new knowledge, insights and, maybe, help.

///H

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ABSTRACT

Background and aims: Systemic sclerosis (SSc) is a multisystem rheumatic disease characterized by fibrosis, vasculopathy and immune system activation.

There is a dearth of knowledge how different subphenotypes such as patients with no–mild and moderate–end-stage lung disease differs in physical function and activity, muscle function and active range of motion. Likewise, no study has yet investigated what experiences patients with SSc have of physical activity and exercise. Although it is known that many patients with SSc have physical disabili- ties, reduced health-related quality of life (HRQoL) and have anxiety and depres- sion symptoms, little is known about differences between patients with no–mild and moderate–end-stage lung disease respectively. The overarching aim of this Thesis was to increase the knowledge of physical function, physical activity and HRQoL in patients with SSc and different degrees of lung disease. The specific aims were to investigate the differences in physical capacity, physical activity, muscle function and range of motion in comparison with population-based controls or reference values. Further, a specific aim was to explore patients’ own experi- ences of physical activity and exercise.

Participants and methods: Three Cross-sectional studies were performed. In paper 1, 106 patients with SSc and 106 age- and gender-matched population- based controls were involved. In paper II, 205 patients with SSc were compared with reference values and in a paper III, 279 patients were involved. Further, a qualitative study with interviews of 16 individuals with SSc were performed and underwent a content analysis.

Results: Paper I: Patients with SSc reported overall lower physical capacity for walking, jogging, and running, and more limiting factors for physical capacity than controls. Patients with no–mild lung disease reported pain more often than their controls, whereas moderate–severe lung disease patients reported cardiopulmonary disease and reduced muscle strength as limiting factors for physical capacity more often than their controls. More patients than controls had ‘never exercised’ for at least 30 min per occasion within the past year; however, there were no differences overall between patients and controls in frequency of exercise, physical activity, nor time spent sitting. Paper II: Shoulder- and hip flexion muscle endurance were lower in relation to reference values, median [53% and 40% of predicted], respectively. Patients with moderate–end-stage lung disease had lower endur- ance in shoulder- and hip flexion [39% and 35%] than patients with no-mild lung disease [57% and 48%]. All patients, regardless subtype/grouping, needed longer time to complete the Timed-Stands Test (TST) [21 s] compared to reference values [17 s], and patients with moderate–end-stage lung disease needed longer time to complete TST than patients with no-mild lung involvement, [25 s vs 19 s]. Active range of motion in shoulder-arm were lower compared with reference values,

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and patients with dcSSc had lower shoulder-arm movement than patients with lcSSc. Paper III: The following three themes (and categories) emerged from the analysis: Essential for life and health (Diminishes symptoms and is as effective as pharmaceuticals, Reduces fear of deterioration, and, Feeling healthy and satisfied with oneself); Disease-related and other hindrances (Breathlessness, pain and other disease consequences limit, Risk of worsening, and, Non-disease barriers); and, Own understanding about physical activity/exercise and support from healthcare (Experience-based knowledge about own capability and physical activity/exercise, and, Education and support from healthcare and others). Paper IV: Patients with moderate–end-stage lung disease scored lower on Medical Outcomes Trust Short Form 36 (SF-36) physical component score than no–mild. Patients with moderate–

end-stage lung disease had lower physical capacity, were less physical active on low-moderate intensity and exercised less the past year compared with no–mild.

Patients with moderate–end-stage lung disease scored higher on Health Assessment Questionnaire (HAQ) and higher scores on Hospital Anxiety Depression scale (HADs), than the no–mild group. In the whole SSc sample, the SF-36 physical component score correlated highly with HAQ and moderately with symptoms on HAQ-VAS- general, dyspnoea, pain; and physical capacity, while SF-36 mental component score correlated moderately with anxiety and depression (HAD).

Conclusions: Although SSc patients reported lower physical capacity and more limiting factors for physical capacity than controls, there were no differences in reported physical activity and time spent sitting. However, SSc patients have mark- edly reduced muscle endurance in both the upper and lower extremities, reduced muscle strength in the lower extremities and impaired active range of motion in the shoulders and arms. Patients with moderate-end stage lung involvement had more impaired muscle endurance and strength than those with no-mild lung involvement but surprisingly no differences were found between lcSSc and dcSSc patients. Among individuals with SSc with both no-mild and moderate–end-stage lung disease, physical activity and exercise was expressed as essential for life and health and that it reduces fear of deterioration. Nevertheless, it was also expressed as a risk for worsening. As patients with SSc with moderate-severe lung disease have lower physical capacity, are less physically active and exercise less, are more physically disabled, have a lower physical HRQoL and have more depressive symp- toms than patients with no-mild lung disease, individualized physical activity and exercise support from physiotherapist might be beneficial. The studies included in this thesis contributes to new knowledge, about how to develop and evaluate future physical exercise programs including resistance training for patients with SSc, especially for those with more severe lung disease.

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SVENSK SAMMANFATTNING

Bakgrund och syften: Systemisk skleros (SSc) är en reumatisk multisystem- sjukdom som karaktäriseras av fibros, vaskulopati och immunsystemsaktivering.

Det råder brist på kunskap hur olika subtyper, som patienter med ingen–mild och måttlig–mycket svår lungsjukdom, skiljer sig i fysisk kapacitet och fysisk aktivi- tet, muskelfunktion och aktivt rörelseomfång. Dessutom finns ingen studie som undersökt vilka erfarenheter patienter med SSc har av fysisk aktivitet och träning.

Även om det är känt att patienter med SSc har fysiska funktionsnedsättningar, nedsatt hälsorelaterad livskvalitet (HRQoL) och problem med ångest och depres- sion, är lite känt om eventuella skillnader mellan patienter med ingen–mild och måttlig–mycket svår lungsjukdom. Det övergripande syftet med denna avhandling var att öka kunskapen om fysisk funktion, fysisk aktivitet och HRQoL hos patienter med SSc och olika grad av lungsjukdom. De specifika syftena var att undersöka skillnader i fysisk kapacitet, fysisk aktivitet, muskelfunktion och rörelseomfång i jämförelse med befolkningsbaserade kontroller eller referensvärden. Ytterligare ett specifikt mål var att utforska patienternas egna erfarenheter av fysisk aktivitet och träning.

Deltagare och metoder: Tre tvärsnittsstudier utfördes. I delarbete 1 inkluderades 106 patienter med SSc och 106 ålders- och könsmatchade kontrollpersoner. I del- arbete II jämfördes 205 patienter med SSc med referensvärden och i delarbete III var 279 patienter inkluderade. Vidare utfördes en kvalitativ studie med individuella intervjuer av 16 personer med SSc där intervjuerna genomgick en innehållsanalys.

Resultat: Delarbete I: Patienter med SSc rapporterade överlag en lägre fysisk förmåga att gå, jogga och springa, och fler begränsande faktorer för fysisk kapa- citet än kontrollpersonerna. Patienter med ingen–mild lungsjukdom rapporterade smärta oftare än deras kontroller, medan patienter med måttlig–svår lungsjukdom rapporterade hjärt-kärlsjukdomar och minskad muskelstyrka som begränsande faktorer för fysisk kapacitet oftare än deras kontroller. Fler patienter än kontrol- ler hade ”aldrig tränat” i minst 30 minuter per tillfälle under det senaste året. Det fanns emellertid inga skillnader mellan patienterna och kontrollerna avseende frekvensen av träning, fysisk aktivitet eller stillasittande under dagen. Delarbete II: Muskeluthålligheten i axel- och höftflexion var lägre än referensvärden, median [53% respektive 40% av förväntade]. Patienter med måttlig–mycket svår lungsjukdom hade lägre uthållighet i axel- och höftflektion [39% och 35%] än patienter med ingen–mild lungsjukdom [57% och 48%]. Alla patienter, oavsett subtyp/gruppering, behövde längre tid för att slutföra Timed-Stands Test [21 s]

jämfört med referensvärden [17 s], och patienter med måttlig–mycket svår lung- sjukdom behövde längre tid för att slutföra testet än patienter med ingen–mild lungsjukdom [25 s vs 19 s]. Aktivt rörelseomfång i skuldra-arm var mindre jämfört

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med referensvärden, och patienter med dcSSc hade mindre skuldra-armrörlighet än patienter med lcSSc. Delarbete III: Följande tre teman (och kategorier) framkom av analysen om fysisk aktivitet och träning: Viktigt för liv och hälsa (Minskar symtomen och är lika effektiv som läkemedel, Minskar rädsla för för- sämring, och, Känner sig frisk och nöjd med sig själv); Sjukdomsrelaterade och andra hinder (Andfåddhet, smärta och andra sjukdomskonsekvenser begränsar, Risk för försämring, och, Icke-sjukdomsrelaterade hinder); och Egen förståelse för fysisk aktivitet/träning och stöd från vården (Erfarenhetsbaserad kunskap om egen förmåga och fysisk aktivitet/träning, och, Information och stöd från vården och andra). Delarbete IV: Patienter med måttlig–mycket svår lungsjukdom hade lägre värden på SF-36 PCS än de med ingen–mild lungsjukdom. Patienter med måttlig–mycket svår lungsjukdom hade lägre fysisk kapacitet, var mindre fysiskt aktiva på låg–måttlig intensitet samt hade tränat mindre det senaste året jämfört med patienter med ingen–mild lungsjukdom. Patienter med måttlig–mycket svår lungsjukdom hade sämre resultat på Funktionsskattningsformuläret (HAQ) och högre poäng på Hospital Anxiety Depression Scale (HAD) än de med ingen–mild lungsjukdom. I hela gruppen korrelerade SF-36 PCS högt med HAQ och måttligt med symtom på HAQ-VAS-allmänt, dyspné, smärta och fysisk kapacitet, medan SF-36 MCS korrelerade måttligt med ångest och depression (HAD).

Slutsatser: Även om patienter med SSc rapporterade lägre fysisk kapacitet och mer begränsande faktorer för fysisk kapacitet än kontroller, fanns inga skillnader i rapporterad fysisk aktivitet och stillasittande under dagen. Patienter med SSc hade emellertid markant lägre muskeluthållighet i både övre och nedre extremiteter, minskad muskelstyrka i nedre extremiteterna och nedsatt skulder-armrörlighet.

Patienter med måttlig–mycket svår lungsjukdom hade lägre muskeluthållighet och mindre styrka än de med ingen–mild lungsjukdom, men överraskande fanns inga skillnader mellan lcSSc och dcSSc. Bland personer med SSc med ingen–mild, och måttlig–mycket svår lungsjukdom, uttrycktes det att fysisk aktivitet och träning var nödvändigt för liv och hälsa, och att det minskade rädslan för försämring. Dock uttrycktes det även att det fanns en risk för negativa konsekvenser av fysisk aktivitet och träning. Eftersom patienter med SSc med måttlig–mycket svår lungsjukdom hade lägre fysisk kapacitet, var mindre fysiskt aktiva samt tränade mindre, hade mer fysiska funktionshinder, hade lägre fysisk HRQoL och mer depressiva symtom än patienter med ingen–mild lungsjukdom, kan individanpassad fysisk aktivitet och träning vara av nytta. Delarbetena som ingår i denna avhandling bidrar till ny kunskap om hur man kan utveckla framtida träningsprogram, inklusive uthållig- hetsträning för patienter med SSc, speciellt för de med svårare lungsjukdom.

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LIST OF SCIENTIFIC PAPERS

I. H Pettersson, A Åkerström, A Nordin, E Svenungsson, H Alexanderson, C Boström. Self-reported physical capacity and activity in patients with sys- temic sclerosis and matched controls. Scandinavian Journal of Rheumatology, 2017, Nov;46(6):490-495

II. H Pettersson, C Boström, F Bringby, R Walle-Hansen, LTH Jacobsson, E Svenungsson, A Nordin, H Alexanderson. Muscle endurance, strength, and active range of motion in patients with different subphenotypes in systemic scle- rosis: a cross-sectional cohort study. Scandinavian Journal of Rheumatology, 2018, Aug 2:1-8

III. H Pettersson, A Nordin, E Svenungsson, H Alexanderson, C Boström.

Experiences of physical activity and exercise in individuals with systemic sclerosis – a qualitative study. Submitted manuscript.

IV. H Pettersson, C Boström, E Svenungsson, H Alexanderson, A Nordin. Health- related quality of life in patients with systemic sclerosis with different degree of lung diseases. A cross-sectional study. Manuscript.

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RELATED PUBLICATIONS NOT INCLUDED IN THE THESIS

de Oliveira NC, Portes LA, Pettersson H, Alexanderson H, Bostrom C. Aerobic and resistance exercise in systemic sclerosis: State of the art. Musculoskeletal Care 2017;15:316-23.

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LIST OF ABBREVIATIONS

ADL activities of daily living AROM active range of motion

COPD chronic obstructive pulmonary disease

DLCO diffusing capacity of the lung for carbon monoxide DU digital ulcers

dcSSc diffuse cutaneous systemic sclerosis FI-2 Functional Index 2

FSA Functional Shoulder Assessment FVC forced vital capacity

GI gastrointestinal tract

HAD Hospital Anxiety Depression scale

HAQ-DI Health Assessment Questionnaire Disability Index HRQoL health-related quality of life

ILD interstitial lung disease

lcSSc limited cutaneous systemic sclerosis MCP metacarpophalangeal

MCS mental component score in SF-36 mRSS modified Rodnan skin score PA physical activity

PAH pulmonary arterial hypertension PAQ Physical Activity Questionnaire PCS Physical component score in SF-36 PFT pulmonary function test

RA rheumatoid arthritis

RP Raynaud´s phenomenon

SSc systemic sclerosis

SF-36 Medical Outcomes Trust Short Form 36 TST Timed-Stands Test

VAS Visual analogue scale

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CONTENTS

1 INTRODUCTION 1

1.1 Systemic sclerosis 1

1.2 Organ manifestations and disease severity 3

1.3 Fibrosis and vasculopathy 3

1.3.1 Fibrosis 3

1.3.2 Vasculopathy 3

1.4 Cardiopulmonary function in SSc 4

1.4.1 Consequences of cardiopulmonary symptoms 4 1.4.2 Assessment of cardiopulmonary function 4

1.5 Range of motion 5

1.5.1 Tight skin 5

1.5.2 Joints 5

1.6 Muscle strength and muscle endurance 6

1.7 Pain and tiredness/fatigue 6

1.8 Disability 7

1.9 Quality of life, anxiety and depression 7

1.9.1 Health-related quality of life 7

1.9.2 Anxiety and depression 8

1.10 Physical capacity and activity 8

1.11 Experiences of Physical activity/exercise 9

1.12 Pharmacological treatments 9

1.13 Non-pharmacological treatments 9

1.14 Clinical outcome measures in SSC 10

1.14.1 Range of motion 10

1.14.2 Muscle function 10

1.14.3 Pain and tiredness/fatigue 11

1.14.4 Disability 11

1.14.5 Health-related quality of life 11

1.14.6 Anxiety and depression 11

1.14.7 Self-reported physical activity/exercise and physical capacity 11

1.15 Qualitative content analysis 12

2 THESIS RATIONALE 13

3 AIMS 14

4 PARTICIPANTS AND METHODS 15

4.1 Study designs 15

4.2 Participants, reference values used in the studies, and procedures 15

4.2.1 Paper I 15

4.2.2 Paper II 17

4.2.3 Paper III 18

4.2.4 Paper IV 18

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4.3 Data analysis 19

4.3.1 Paper I 19

4.3.2 Paper II 19

4.3.3 Paper III 19

4.3.4 Paper IV 21

4.4 Ethical approval 21

5 RESULTS 22

5.1 Paper I: Self-reported physical capacity and activity 22 5.2 Paper II: Muscle endurance, strength and active range of motion 24 5.3 Paper III: Experiences of physical activity and exercise 27

5.4 Paper IV: Health-related quality of life 30

6 DISCUSSION 35

6.1 Main findings 35

6.2 Physical activity and exercise 35

6.3 Patients experiences of physical activity and exercise 36

6.4 Physical function 37

6.5 Health-related quality of life 38

6.6 Scoring of lung disease severity 38

6.7 Methodological considerations 39

6.8 Concluding remarks and future perspectives 41

6.8.1 Conclusions Papers I – IV 42

6.8.2 Future research 43

7 ACKNOWLEDMENTS 44

8 REFERENCES 46

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1 INTRODUCTION

1.1 Systemic sclerosis

Systemic sclerosis (SSc) is a rare autoimmune systemic disease characterised by vas- culopathy, fibrosis and autoimmunity [1,2]. The American Rheumatism Association published the first classification criteria for SSc in 1980 [3]. The criteria were revised and updated by the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) [4], (Table 1). The classification criteria include the skin, lesions, abnormalities in blood vessels, cardiopulmonary manifestations like pulmonary arterial hypertension (PAH) and lung fibrosis/interstitial lung disease (ILD). A total score is calculated through adding the maximum score in each of the eight sub-items. Patients with total score ≥9 are considered to have definite SSc.

Tight skin on fingers on both hands extending proximal to the metacarpophalan- geal (MCP) joints is considered as a sole criterion for SSc. Based on the extent and location of skin involvement SSc is traditionally grouped into two distinctive subtypes; limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) [5-7].

In patients with lcSSc skin tightness is limited to parts distal to elbows or knees, whereas those with dcSSc have more widespread skin changes affecting proximal limbs and/or trunk. Face involvement can be present in both subtypes [6,7]. This clinical classification can be considered as a help to classify patients according to presence and extent of skin involvement, and also to predict future internal organ disease and survival [6].

Raynaud’s phenomenon (RP) is together with involvement of the gastrointestinal tract (GI) the first symptoms of SSc and they are almost universal in both subtypes of the disease [6].

Recent research highlights the importance of investigating the presence of anti- nuclear antibodies (ANA) in patients with SSc, since the autoantibody pattern helps to improve diagnosis and identification of disease subsets as wells as to improve patient’s care and management [8,9]. Over 90% of patients with SSc display ANA [1,10]. The most common and clinically relevant subsets of ANA in SSc are anti- topoisomerase I antibodies (ATA) and anti-centromere antibodies (ACA) [1,10]. In Caucasian populations ACA is more common than ATA, occurring in up to 90% and 40% respectively [10-12]. The presence of ANA is often present prior symptom onset and titres of ANA are often stable during the course of the disease [6]. The ANA- subgroups are in most cases associated with different clinical patterns of disease.

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Table 1. The American College of Rheumatology/European League Against Rheumatism criteria for the classification of systemic sclerosis (SSc) [4].

Item Sub-item(s) Score

Skin thickening of the fingers of both hands extending proximal to the MCP joints (sufficient criterion)

- 9

Skin thickening of the fingers (only count the highest score)

Puffy fingers

Sclerodactyly of the fingers (distal to the MCP but proximal to the interphalangeal joints)

2 4

Fingertip lesions (only count the highest score)

Digital tip ulcers Fingertip pitting scars

2 3

Telangiectasia - 2

Abnormal nailfold capillaries - 2

PAH and/or ILD (maximum score is 2) PAH ILD

2 2

RP - 3

SSc-related ANA’s (maximum score is 3) ACA ATA A-RNA III

3 3 3

MCP: metacarpophalangeal; PAH: pulmonary arterial hypertension; ILD: interstitial lung disease;

RP: Raynaud´s phenomenon; ANA: anti-nuclear antibodies; ACA: anti-centromere antibodies;

ATA: anti-topoisomerase I antibodies; A-RNA III: anti-RNA polymerase III antibodies. The total score is determined by adding the maximum score in each category and a total score ≥9 is considered as having definite SSc.

The incidence and prevalence of SSc varies globally depending on regions and ethnicity. The reported incidence varies between 4–43 per million and the preva- lence between 70–340 per million [13]. In a study published 2014 [14], including all residents in Skåne, the southernmost region of Sweden with a population of 1.3 million inhabitants, the adult annual incidence and prevalence of SSc were 14 and 235 per million, respectively. Between 60–80% of the patients worldwide are diagnosed with lcSSc, while approximately 20–40% of patients have dcSSc [2,5]. The Swedish study showed that 82% of the prevalent cases were diagnosed with lcSSc [14]. As in many other rheumatic diseases female gender predominates in patients with SSc with a female/male ratio of 6:1 [1], however the gender ratio differs between the two diagnostic subgroups with a ratio of 11:1 in lcSSc and 4:1 in dcSSc [1].

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1.2 Organ manifestations and disease severity

Several different organ systems can be affected in SSc, and the extent of disease damage and disease severity is often assessed by the Medsger disease severity scale [15] which grades nine areas affected by the disease: (1) General, (2) Peripheral Vascular, (3) Skin, (4) joint/tendon, (5) Muscle, (6) Gastrointestinal tract, (7) Lung, (8) Heart and (9) Kidney. The scale measures disease damage between 0, indicating normal function/no impairment or damage, to 4, end-stage. The end-stage score of 4 points means that a patient is dependent of supplemental oxygen if the score 4 occurs in the organ system Lung, and when a 4 is scored in the organ system Heart it means that the patient is suffering from congestive heart failure and has a left ventricular ejection fraction of <30%.

Skin thickness is usually measured by the modified Rodnan skin score (mRSS) [16]. The mRSS is also included in the Medsger disease severity score as part of the organ system Skin [15].

1.3 Fibrosis and vasculopathy

1.3.1 Fibrosis

Fibrosis of the skin is one of the hallmarks of SSc and the term scleroderma, hard skin, is used to describe the hard woody like skin feature [17]. The fibrotic changes do not only affect the skin but also different internal organs such as the GI, the lungs and the heart [6]. Diffuse cutaneous SSc is associated with earlier occur- rence of severe lung fibrosis/ILD, cardiac fibrosis and an overall worse prognosis.

The ILD is due to thickening of the interstitium caused by autoimmunity and/or inflammatory processes [2,5,18–20].

1.3.2 Vasculopathy

The vascular spasm in RP is episodical, painful, and mainly affects fingers or toes but also the nose and ears. The ischemia is mainly provoked by exposure to cold temperatures, changes in temperatures and/or stress [6,21]. More than 50% of patients have a history of digital ulcers, and approximately 10% of all patients with SSc currently have digital ulcers [22]. The pathophysiology of digital ulcers is multi- fold, and often vasospasm and vasculopathy (e.g. intimal fibrosis and endothelial dysfunction) are contributing factors [23]. Not only are ulcers very painful, digital ulcers also take a very long time to heal [22]. The most feared and severe form of vasculopathy is PAH [23,24]. Albeit patients with SSc can be affected by all forms of pulmonary hypertension, PAH is the most common type [25]. The vas- cular disease in the lungs in SSc is characterized by narrowing and occlusion of the pulmonary arteries. The risk factors for developing isolated PAH are long disease duration, presence of ACA and the belonging to the lcSSc subtype [26].

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1.4 Cardiopulmonary function in SSc

1.4.1 Consequences of cardiopulmonary symptoms

Lung fibrosis and PAH are two common and serious consequences of the disease, both leading to a decline in lung function [23,27]. They are potentially lethal com- plications and the most common causes of death in SSc [6,28] with lung fibrosis- related mortality in 19%, isolated PAH in 14% followed by myocardial (overall) causes in 14% [28].

Dyspnoea is a cardinal symptom of both ILD and PAH and indicate a more severe form of disease, however, dyspnoea at exertion can also be a symptom of decondi- tioning due to inactivity [29]. Regardless of origin, dyspnoea, or shortness of breath/

breathlessness is often experienced by patients with SSc [30].

1.4.2 Assessment of cardiopulmonary function

The use of high-resolution computed tomography (HRCT) is a well-established method to assess signs of lung fibrosis/ILD in SSc [6,25,31]. Clinically relevant lung fibrosis is present in approximately 25% patients with SSc [25] but fibrosis/

ILD is observed in up to 90% of cases with SSc, if also subclinical lung fibrosis/

ILD is included [32].

By use of pulmonary function tests (PFT) the presence, and severity, of fibrosis can be detected [33]. The forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) are both important variables. Values ≥80% of pre- dicted FVC and DLCO are considered as normal in individuals without respiratory limitations [25], however, PFT also have certain disadvantages as the normal range of FVC is 80–120%. In cases where patients have an FVC and/or DLCO >80% of predicted values, but present progression of respiratory problems further evalua- tions are needed [25,32]. The spirometry variable FVC [34] is a useful measure to predict prognosis and mortality in patients with lung fibrosis [26]. The risk factors for developing severe ILD are early dcSSc and ATA, especially in patients that have a reduction in FVC during the first 18 months since disease onset. Unlike idiopathic ILD the decline in FVC may stabilize around 60–70% of predicted values for many years [26]. Pulmonary function tests assessing DLCO [35] and transthoracic echo- cardiography are recommended as to screen all patients with SSc for PAH [36].

1.4.2.1 Lung disease severity scale

The Medsger Disease Severity scale combines findings from PFT (DLCO and FVC) with the classification of (no)/presence of fibrosis on HRCT and elevated pulmonary arterial pressure to assess lung disease severity in SSc [15] (Table 2). Each measure is scored using the most severe of the included values in the scoring. In this Thesis patients with a score of 0–1 on the Medsger scale were classified as having no–mild lung disease and those with 2–4 as having moderate–end-stage lung disease.

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Table 2. Disease severity of the lungs, according to the Medsger scale [15].

Organ system

0 (normal)

1 (mild)

2 (moderate)

3 (severe)

4 (end-stage) 7. Lung DLCO ≥ 80%,

FVC ≥ 80%, No fibrosis on radiograph, sPAP <35 mmHg

DLCO 70–79%, FVC 70–79%, basilar rales, Fibrosis on radio- graph, sPAP 35–49 mmHg

DLCO 50–69%, FVC 50–69%, sPAP 50–64 mmHg

DLCO <50%, FVC <50%, sPAP 65+ mmHg

Oxygen required

DLCO: diffusing capacity for carbon monoxide, % of predicted; FVC: forced vital capacity,

% of predicted; sPAP: estimated pulmonary arterial pressure by Doppler transthoracic echocardiography.

1.5 Range of motion

1.5.1 Tight skin

The skin changes in SSc may present in three phases where the initial phase is an inflammatory and oedematous stage where the fingers and hands appear puffy and swollen. In the second and longer phase various degree of sclerotic progres- sive skin fibrosis occur, typically starting distal to the MCP joints. During this phase contractures in fingers and hands start. In the third phase, skin is gradually becoming softer and atrophic. The skin may return to a state of clinical normality, especially on the upper extremities and the trunk [6,37]. The tight skin may restrict active range of motion (AROM) in both upper and lower extremities [38,39]. Tight skin around the mouth can appear in both subtypes, and the characteristic micro- stomia which limits mouth opening is present in about 70% patients [40]. Excess fibrotic tissue makes the skin hard and can impact facial mimicry and make oral care problematic [37]. Subcutaneous fat can also dwindle or disappear in both the face as well as the hands and feet [6,7]. The changes in appearance is problematic, especially among women [37].

1.5.2 Joints

Progressive skin thickening/changes can give rise to contractures affecting mainly the fingers/hands in SSc. Joint involvement, both presented as generalized arthralgia with stiffness and slight pain as well as inflammatory arthritis, eventually affects between 46–97% of all patients with SSc [41]. These alterations can cause reduc- tions in grip strength and impaired dexterity [6,38]. Joint contractures affect about 1/3 and causes functional disability due to skin sclerosis, tendon shortening and/

or joint destruction [42]. Several studies have shown that patients with dcSSc, but also lcSSc, are affected by severe AROM impairments [43–45]. In addition, contractures (reductions in ROM <75% of normal values), are very common in wrists and hands affecting more than 75% of patients with SSc. Larger joints like

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the shoulders are affected in 50% in flexion-extension, abduction-adduction in 15% while contractures are found to a lesser extent in the lower extremities, in approximately 10% in hip, knee and ankle [44,46]. Limited AROM in the lower extremities has also been found in SSc, especially in dcSSc [39,47]. Yet, there is limited insight on the impact of lcSSc/dcSSc to what extent functional AROM in activities of daily living (ADL) is affected in the shoulder-arm region and whether this influence the possibilities to be physically active (PA) and exercise.

1.6 Muscle strength and muscle endurance

Muscle involvement in SSc varies widely but is reported to be present in between 5–96% of patients [48] and is more common in dcSSc than in lcSSc [1,48].The big diversity in reported frequency is mainly due to different methods when assessing muscle involvement and also lack of consistently accepted definition of myopathy [48]. Proximal muscle weakness in shoulder and hip-pelvic region is a prominent symptom in SSc [6,49]. Functional strength, as in standing up from a sitting posi- tion, is also reduced in comparison with normative data. Differences between subtypes of SSc are present as patients with lcSSc can perform more sit-to-stand movements than patients with dcSSc. Patients with SSc were more limited in the timed up and go test compared to normative data [39]. Muscle endurance in the quadriceps muscles has also been found to be reduced in comparison with con- trols [50]. Others have used tests like the Keitel functional test, and the 30-second timed sit-to-stand, that both measures muscle function in the lower extremities [39]. Muscle strength as well as muscle endurance can also be assessed with an isometric dynamometer [50]. Nonetheless, there is a dearth of knowledge about how muscle strength and muscle endurance is affected, especially in patients with different degrees of lung disease, and what consequences muscle impairment has in the lives of patients with SSc.

1.7 Pain and tiredness/fatigue

Pain is a common symptom in patients with SSc [30] with arthralgia and myalgia among the earliest musculoskeletal symptoms [6]. The frequency of self-reported pain has been reported as ~85% in joints, ~75% in muscles as well as ~55% in skin [30]. Pain originating from RP is one of the most frequently reported symp- toms in SSc [30,51]. Furthermore, digital ulcers are also very painful [22]. There is a lack of knowledge on how patients with SSc perceive pain in relation to PA/

exercise and physical capacity and whether there are any differences in regard to lung involvement. Fatigue is another disease-related symptom affecting many patients with SSc. This overwhelming tiredness is not only very frequent, but also one of the symptoms with highest impact on everyday activities [30]. Severe fatigue is associated with more pain, worse sleep quality and greater depressive symptoms [52].

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1.8 Disability

Due to the heterogenous nature of SSc different degree of limitations in function can be encountered. Primarily the hands are affected but also the face is affected by local disability [37]. Among patients with SSc ADL can be a major problem as finger flexion and extension and grip strength has been found to be impaired in comparison with healthy persons [38]. Not only activities involving the upper extremities, like dressing or lifting/holding objects and other household activities, are affected, the lower extremities are also influencing the possibilities to partake in activities. It has been reported that climbing stairs, getting in/out of a car and leisure activities like sports are troublesome [30,53].

Patients with dcSSc have more disabilities compared to patients with lcSSc when assessed with the Health Assessment Questionnaire Disability Index (HAQ-DI) [54,55]. There are little if any correlations between FVC and DLCO and HAQ-DI but a moderate correlation has been presented between dyspnoea and HAQ-DI [56]. Yet no study has evaluated the impact of lung disease, as measured with the Medsger disease severity scale, on disability in SSc.

1.9 Quality of life, anxiety and depression

1.9.1 Health-related quality of life

The World Health Organization defines quality of life as an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. It is a broad ranging concept affected in a complex way by the person’s physical health, psychological state, personal beliefs, social relationships and their relationship to salient features of their environment [57].

The term quality of life is, in the same way as health is, ambiguous and not easily given a distinct definition. Both concepts are reflecting different aspects of well- being, but the quality of life has a considerably broader content. Health-related quality of life (HRQoL) means a pragmatic delimitation, and primarily relates to function and well-being during illness and treatments [58].

Measurements of HRQoL can be done with different self-reported questionnaires, but the generic Medical Outcomes Trust Short Form 36 (SF-36) is probably the most well-known and used tool, in SSc as well as in other populations and samples. The HRQoL, as measured by SF-36, has been found to be lower among patients with SSc compared with the general population, and patients with dcSSc have lower HRQoL than lcSSc [59]. Patients with dcSSc report lower scores on physical and mental aspects of HRQoL compared to patients with lcSSc [60]. Dyspnoea has been found to correlate with HRQoL whereas no correlations were found with objective lung damage in a study with lcSSc without signs of PAH [56]. Another

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study reported that patients with SSc with ILD, and patients with chronic obstruc- tive pulmonary disease (COPD) have lower scores in the physical HRQoL in relation to the general population [61]. So far, no study has evaluated the HRQoL in patients with different degrees of lung disease as measured with the Medsger disease severity scale.

1.9.2 Anxiety and depression

Due to the reduced life expectancy in dcSSc, which is associated with internal organ involvement [62] it is understandable that anxiety and depression symptoms are common in SSc [63]. Clinically relevant self-reported anxiety is more frequently reported in women, whereas men are more often free from symptoms of both anxiety and depression when measured with the Hospital Anxiety and Depression scale (HAD) [64]. If levels of anxiety and depression symptoms differ depending on degree of lung involvement as measured with the Medsger score is unknown.

1.10 Physical capacity and activity

In this Thesis we define physical capacity as self-reported ability to walk, jog or run. Physical activity (PA) has been defined as any bodily movement that is pro- duced by skeletal muscles and resulting in an energy expenditure. PA in the daily living can be categorized into household, occupational, conditioning, sports, or other activities. Exercise is a subset of physical activity that is planned, structured, and repetitive and has, as a final or an intermediate objective, the improvement or maintenance of physical fitness. Physical fitness is a set of attributes that are either health- or skill-related [65].

Reduced PA has been observed in patients with early SSc without pulmonary involvement, and nearly ¾ were below recommended levels of PA in compari- son to only 27% of age- matched controls [66]. Likewise, in patients with lcSSc and with PAH reduced PA has been reported in comparison with patients without PAH [67]. Self-reported PA has also been found to be significantly lower among patients compared to the general Dutch population [68]. There are yet no publica- tions presenting results whether there are any differences in PA between patients with no–mild and moderate–end-stage lung disease, nor between patients and true age- and gender-matched controls.

Patients with SSc without lung involvement have a significantly lower aerobic capacity compared with healthy controls as measured by maximal exercise test on a treadmill [69]. Likewise did maximal ergometer testing show that patients with PAH had lower maximal oxygen uptake than patients without PAH, but both groups had a clear limitation in exercise performance when compared to predicted values [70]. How self-reported physical capacity is perceived in patients with SSc with different degrees of lung involvement, and if there are any differences between groups, remains unknown.

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1.11 Experiences of Physical activity/exercise

In other chronic rheumatic diseases, such as rheumatoid arthritis (RA), PA/ exercise have been reported to be perceived as important contributors to symptom manage- ment including pain relief and joint function. Both pain and fatigue as well as reduced mobility and stiffness have been reported as barriers to PA/exercise in RA [71]. Similar findings are presented in ankylosing spondylitis (AS) where pain, stiffness and fatigue were the main barriers to PA/exercise while the most often reported benefits of PA/exercise were improved fitness, increased vitality and improved mood [72]. Shortness of breath is experienced as a major barrier for PA/exercise in patients with pulmonary diseases such as COPD, while feel- ing fit and having better breathing outcomes, and support from others, like health professionals such as physiotherapists, were facilitating factors [73].

However, very little is known about how patients with SSc perceive PA/exercise, and what experiences they have from being PA/exercise, nor what is considered as facilitating and hindrances.

1.12 Pharmacological treatments

There are no curative treatments available for patients with SSc, however, many of the different symptoms can be alleviated by pharmacological drugs [7]. Intensive research is underway, and many patients have already had their disease burden eased by use of immunosuppressive treatments as well as blood vessel modulat- ing treatments [7].

1.13 Non-pharmacological treatments

In the newly revised recommendations for Modern Rheumatological Rehabilitation (MoRR) the aims of rehabilitation in rheumatic diseases are to regain and/or maintain physical function and participation in society [74]. This can be done by prevention, needs-driven individual interventions, team rehabilitation in an out- ward setting, and after this, in an in-ward setting. Regardless rehabilitation level physiotherapists are key-players as they, as well as PA/exercise, are fundamental in the rehabilitation of patents with rheumatic diseases [74].

Because no curative pharmacological treatments are available for patients with SSc rehabilitation is a possible way to ease the disease burden. However, there is limited knowledge and guidelines about non-pharmacological care in SSc, mainly because of the large variety in studied interventions as well as in the outcomes.

Furthermore, the studied samples are in many cases small and/or lacking control groups [37,75]. Our research group, in collaboration with Brazilian researchers, have in a literature review found that physical exercise in patients with SSc with no or mild lung disease has shown positive effects concerning physical capacity,

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HRQoL and could be considered safe [76]. However, there are few studies [76]

concerning the effects of exercise in patients with SSc with moderate to severe lung disease. But improvements in aerobic capacity [77] and muscle endurance [78] have been reported in patients without ILD after participation in exercise programmes. In a small study in patients with SSc with and without pulmonary involvement, increased muscle strength and aerobic capacity was seen after 12 weeks resistance and aerobic exercises [79]. The aims in hand rehabilitation are to improve both movement and strength in hands, and ameliorate participation in ADL like personal self-care, house-hold activities and leisure activities [37].

Different techniques to treat musculoskeletal impairments have been used with various results [80]. Hand stretching was beneficial [81], as was connective tissue massage [82]. Paraffin wax bath in combination with hand exercise has also been found to improve function more than sole exercise [83].

1.14 Clinical outcome measures in SSC

1.14.1 Range of motion

Goniometer is often used by physiotherapists, as well as occupational therapists, when measuring active and passive ROM, as has been used in previous studies [44,46,84]. Another way to assess AROM in the upper extremities in rheumatic diseases is with the Functional Shoulder Assessment (FSA) [85]. This instru- ment was originally developed for patients with RA. In the original version of FSA four tasks were assessed [85], but a revised version with five tasks has been developed [86].

1.14.2 Muscle function

Muscle strength, and muscle endurance, can be measured in different ways. An isometric muscle test measures muscle function in a static position, the muscle tries to contract but does not change in length, whereas in an isotonic muscle test the muscle changes in length. Functional muscle strength in the lower extremities can be measured with the Timed-Stands Test (TST) [87]. Another, similar test, is the 30-second timed sit-to-stand, that also measures muscle function in the lower extremities [88]. The Timed Up and Go test can also be used as a physical fitness test for assessing agility/dynamic balance [89].

Muscle strength has often been measured by use of the manual muscle test (MMT), however this instrument is limited by ceiling effects in patients with mild muscle strength weakness [48]. Dynamic repetitive muscle endurance can be measured with Functional Index-2 (FI-2), an instrument originally developed for patients with myositis [90].

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1.14.3 Pain and tiredness/fatigue

Pain can be assessed in various ways, either by use of a numeric rating scale [91], visual analogue scale (VAS) [92], or self-reported HRQoL such as in SF-36 [58].

Assessments of fatigue can be done with several different questionnaires [93,94].

1.14.4 Disability

The HAQ instrument is a self-reported questionnaire that has become one of the key instruments used when assessing disability and function in rheumatic musculoskeletal disorders. Included in the HAQ is a disability index (HAQ-DI).

The HAQ-DI has been adopted to the context of SSc, Scleroderma HAQ (SHAQ) by having five VAS added [95], otherwise than this both HAQ and SHAQ are scored the same way [96]. The five VAS measures pain, patient general assessment, vascular, digital ulcers, lung involvement and gastrointestinal involvement [95,96].

1.14.5 Health-related quality of life

There are several instruments that are used to assess HRQoL, both generic and diseases/symptom-specific. One generic is the EuroQol instrument, subsequently called EQ-5D [97] and another is the well-known Medical Outcomes Study 36-short form (SF-36) [98]. The St George’s Respiratory Questionnaire (SGRQ) was originally developed to assess HRQoL in patients with COPD but it has also been used in patients with idiopathic pulmonary fibrosis [99].

1.14.6 Anxiety and depression

The HAD scale was developed to identify possible and probable cases of both anxiety and depression disorders. The HAD scale consists of seven questions each for the anxiety dimension (HADa) and depression dimension (HADd) [100]. In an attempt to prevent disturbances from physical disorders like insomnia, dizziness, fatigue and headaches, symptoms that were related to anxiety and/or depression were excluded from the scale [100].

1.14.7 Self-reported physical activity/exercise and physical capacity

Self-reported physical activity has often been assessed by the International Physical Activity Questionnaire and there are different versions of the instrument available, and also various forms of administration of the questionnaire; as by telephone interviews or by self-administration [101]. Another self-reported questionnaire is the Physical Activity Questionnaire (PAQ) that has been used in systemic lupus erythematosus (SLE) in Sweden [102,103]. The latter questionnaire also assesses exercise, physical capacity along with time spent sitting during day.

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1.15 Qualitative content analysis

Experiences of PA/exercise are preferably explored with qualitative research methods as this approach may facilitate a more in-depth understanding of a group of individuals experiences [104]. By using a qualitative method, it is possible to evaluate and gain a deeper understanding in different perspectives [105]. The inquisitive use of qualitative methods can be used when there is insufficient, or a lack of information about a certain topic like how patients with SSc experience PA/exercise. Content analysis is an often-used method in nursing and healthcare research [106,107]. A face-to-face interview can often last between 30 and 90 minutes. Use of a semi-structured interview guide is recommended as it enhance the topics of interest that will be covered by every informant. About 15–20 individual interviews or three-to-four focus group discussions are often enough, depending on data saturation [108].

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2 THESIS RATIONALE

Systemic sclerosis is a major cause of disability and increased morbidity as well as mortality. The large diversity of how the disease presents itself; lcSSc/dcSSc, quick progression or stable disease, damage of varying severity in different organ systems, combined with the rarity makes it challenging to both study the disease, and to adequately treat the patients.

Little is known about how, and if, self-reported levels of physical capacity and PA/exercise differ between patients with no–mild and moderate–end-stage lung disease. Likewise, there is a dearth of knowledge as to what extent muscle function and AROM is affected in different subphenotypes of SSc. Nothing has yet been published about how patients with SSc experience PA/exercise, nor what factors are perceived as facilitating, or as hindrances. However, it is well known that patients with SSc have reduced HRQoL, that they often have disabilities affecting their ADL, and that they suffer from symptoms of both anxiety and depression.

But less is known about differences/similarities between patients with no–mild and moderate–end-stage lung disease.

Increased knowledge about physical capacity, levels of PA/exercise on different levels of intensity in addition to further knowledge about how much muscle strength, muscle endurance and AROM is affected in SSc, can help develop exer- cise programs suitable for patients with different degrees of lung disease. Also, by increased insight into how patients experience PA/exercise and what they perceive as facilitating and/or hindrances can improve patient education and support to those in need. With the aim to optimize health for patients with SSc, PA/exercise is an important, and often neglected, addition to medical treatment. This taken together, can hopefully help to increase HRQoL in patients with SSc.

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3 AIMS

The overarching aim of this Thesis was to increase knowledge about physical function, physical activity and quality of life in patients with SSc and different degrees of lung disease.

The aims of the included papers were:

I. To investigate potential differences in self-reported physical capacity and activity between patients and an age- and gender-matched population-based control group, as well as between patients with normal–mild and moderate–

severe lung disease and their respective controls.

II. To examine functional dynamic muscle endurance in the shoulder and hip- girdle, functional dynamic muscle strength in the lower extremities, and functional AROM of the shoulder-arm region in patents with SSc.

We also explored possible differences depending on SSc subphenotypes; i.e.

lcSSc versus dcSSc, and presence of mild versus severe lung involvement.

III. To explore and describe experiences of PA/exercise in individuals with SSc.

IV. To explore differences/similarities with focus on HRQoL, disabilities, PA/

exercise and physical capacity between patients with no–mild lung disease and moderate–end-stage lung disease.

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4 PARTICIPANTS AND METHODS

4.1 Study designs

In the papers included in the Thesis, different research designs were used, see Table 3.

Table 3. Overview of the research designs of the papers included in the Thesis.

Paper Design Specific analysis methods a

I Cross-sectional cohort study compared with an age- and gender matched population-based controls

Pearson’s ᵡ2 or Fisher’s exact test, Mann-Whitney unpaired test, Student’s t-test.

II Cross-sectional cohort study

compared with reference values Pearson’s ᵡ2 or Fisher’s exact test, Mann-Whitney unpaired test, Wilcoxon signed-ranks test.

III Interview study using exploratory

descriptive qualitative design Content analysis, inductive approach IV Cross-sectional cohort study

compared with reference values Pearson’s ᵡ2 or Fisher’s exact test, Mann-Whitney unpaired test, independent samples t-test, Spearman’s correlation coefficient

a descriptive statistics were used in all papers in the Thesis.

4.2 Participants, reference values used in the studies, and procedures

All patients with SSc are part of the Karolinska University Hospital’s SSc-cohort, which consists of patients living in the greater Stockholm region. Demographic and clinical characteristics are presented in Table 4.

4.2.1 Paper I

A total of 106 adult patients with SSc and 106 age- and gender-matched popu- lation-based controls living in the Stockholm County were included. All partici- pants were recruited between 2006 and 2009. The control persons were recruited by use of the national identification number which is coded for gender and date of birth. The gender-matched person with the birth date closest to the respective patient was contacted and asked to participate in the study. If the “first choice”

declined participation, the second closest was asked, until control person gave her/his consent. In 65 % of cases the “first choice” accepted and participated in the study. The only exclusion criterion was a diagnosis of SSc. All patients, and controls, answered the PAQ.

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The PAQ instrument covers different self-reported aspects of physical capacity, PA and time spent sitting as well as exercise. The PAQ used in this Thesis have moderate to almost perfect test-retest reliability (weighted kappa coefficients 0.55–0.87) as suggested by Landis and Koch [109] and satisfactory content validity in patients with SLE [103].

As part of this Thesis the test-retest reliability of the PAQ was performed on a subgroup (n=51) of patients with SSc. The test-retest reliability was moderate to substantial. The questions regarding PA on a low-moderate intensity past six months had a weighted kappa: 0.57, 95% CI (0.39–0.81), PA on a high intensity past Table 4. Demographic and clinical characteristics of patients included in the Thesis.

Characteristics Paper 1 Paper II Paper III Paper IV

Participating patients and

controls, n 106+106

controls 205 16 279

Age, years 61±12 60 (52–69) 53 (24–73) † 60 (52–69)

Women, % 84 82 81 83

LcSSc/dcSSc, % 79/21 82/18 75/25 84/16

No–mild/moderate–end- stage lung disease, %

55/45 59/41 50/50 58/42

Disease duration, years 9±9 8 (3–13) 8 (1–38) † 5 (2–11)

Medsger disease severity General, % ‡

na 88/10/1/0/1 na 89/10/1/0/06

Peripheral vascular, % ‡ na 17/61/13/8/12 na 14/62/13/10/17

Skin, % ‡ na 9/81/9/1/0 na 10/83/6/1/0

Gastrointestinal, % ‡ na 30/55/13/1/113 na 28/59/12/1/016 Lung, % ‡ 28/26/34/10/2 27/31/29/12/16 19/31/31/6/13 28/30/29/12/18

Heart, % ‡ na 80/14/2/2/26 na 81/14/3/1/112

Kidney, % ‡ na 95/4/9/1/13 na 94/4/0/1/18

Pulmonary hypertension, % 8 6 na 81

Lung fibrosis, % 46 38 na 401

DLCO (% of predicted), % 72±195 na na 74 (61–86)10

FVC (% of predicted), % 84178 na na 87 (76–98)12

Values are presented as mean±(SD), % or median (IQR); †: Median (min-max); ‡: Medsger disease severity score 0/1/2/3/4; DLCO: diffusing capacity of the lung for carbon monoxide;

FVC: forced vital capacity

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6 months: 0.66, 95% CI (0.35–0.96), Physical capacity: 0.58, 95% CI (0.42–0.74), Time spent sitting during the day: 0.74, 95% CI (0.47–1.0), and, Exercise past year: 0.74, 95% CI (0.52–0.96).

4.2.2 Paper II

In this study 205 patients with lcSSc/dcSSc were divided into no–mild and moderate–end-stage lung disease. All patients who had performed physical assess- ments at the physiotherapy department at the Unit of Rheumatology at Karolinska University Hospital, Solna, between September 2006 and May 2017 were included.

The FSA was used to measure AROM in the shoulder-arms, FI-2 assessed dynamic muscle endurance in upper and lower extremities, TST was used to measure func- tional muscle strength in the lower extremities.

For FSA, reference values from the general Swedish population, in intervals of 10 years, was used. These reference values are presented by Olofsson et. al. [110]

and in the present study we had access to their original data. In the Olofsson-study they used an earlier version of FSA which consisted of four tasks. The included tasks are assessed on a 6-point Likert scale (1 point being the worst possible func- tion and 6 points is no impairments in AROM), resulting in a total maximum score of 24 points per shoulder-arm in the 4-task version and 30 points in the 5-task ver- sion. Also, in the original FSA, the task Hand-to-neck was scored as 1–7 points, we converted this part to 1–6 points as it is scored this way in the most recent version. In this new version the task hand-to-seat has been added giving a total of 30 points for each shoulder. The comparison of results in the patient group and subjects from the general Swedish population was done by using results previ- ously presented by Olofsson et. al. [110] in intervals of ten years which used the 4-task version of FSA. When comparing different subphenotypes of patients with SSc we used the newer, 5-task version of FSA [86].

The FI-2 is commonly used in clinical settings in Sweden. Seven different muscle groups can be assessed and graded separately. In the Thesis shoulder flexion and hip flexion were assessed. The shoulder flexion was assessed in a sitting position with a 1 kg weight cuff around the wrist. The hip flexion was assessed in a supine position with a straight leg. A pace of 40 beats/minute resulted in a pace of 20 repetitions/minute. The maximal number of repetitions (60 per shoulder and leg) was registered. The results can be presented as counts or percentages of maximal repetitions per task. Preliminary reference values have been collected at Karolinska University Hospital, Solna, Sweden (HA), and at the Oslo University Hospital, Norway (RWH). These reference values are based on age intervals of 10 years from the general population. The comparison of patients’ FI-2 results with refer- ence values was done on the right side only, due to 88% of reference values being assessed on the right side.

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The FI-2 has been found to have “good” to “excellent” intra-rater, and, inter-rater reliability and it does also have a good construct validity in patients with myositis [90], however the test has not been validated in SSc yet.

For the TST, the time needed to complete ten full stands, without help from the hands, from a sitting position is recorded. Reference values for TST, based on gender- and age-matched healthy subjects, in intervals of 5 years, was used when comparing with patients’ assessments. The TST has been validated in several rheumatic and other chronic diseases [111].

4.2.3 Paper III

Sixteen patients strategically identified to represent both lcSSc/dcSSc and no–

mild and moderate–end-stage lung disease as well as both sexes, various age, and disease duration were interviewed between August 2017 and February 2018. The individual interviews were performed at a secluded room at Karolinska University Hospital, Solna. Each interview took in average 30–60 minutes.

4.2.4 Paper IV

In this study 279 patients were included between September 2006 and December 2018. To be included in the study the participants had to understand Swedish well enough to be able to fill in at least two of the four questionnaires used. The questionnaires used were SF-36, HAQ-DI including the five SSc-specific VAS, PAQ, and HADa/d.

The generic HRQoL questionnaire SF-36 assesses four physical health domains;

Physical Function, Role Physical, Bodily Pain, General Health, and four mental health domains; Vitality, Social Function, Role Emotional, and Mental Health.

Each domain is scored separately using an item weighting and additive scale. The summed data are then transformed onto a 0–100-point scale. The higher score, the higher quality of life. The scores can be added into global scores; physical component score (PCS) and mental component score (MCS) [98]. The PCS and MCS are standardized to responses from the general Swedish population and they have a mean score of 50 and a standard deviation of ±10 [112].

The HAQ-DI comprises 20 items that are divided into eight functional domains, each of which has two or three component questions adding up to a total of 20 items.

The overall score is calculated by adding the highest item score in each of the eight functional domains and then dividing the sum by eight resulting in a score range between 0–3, where 0 means no disability whereas 3 indicate severe disability. The VAS measures self-reported problems the past week; pain, intestinal, breathing, RP and digital ulcers, and also, overall problems today. The within-patient test-retest has been found to be very good, and the validity is also very high [96].

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Both the anxiety and depression dimensions that are part of HAD have seven questions each, and each question is scored between 0–3. The total score in each dimension ranges from 0, no clinical symptoms of anxiety or depression, to 21, maximal clinically significant symptoms. Scores between 0–7 are considered as normal, between 8–10 as borderline, and 11 or more as clinically relevant [100].

The instrument has been used in several studies in SSc, but it has not been specifi- cally tested for reliability or validity in SSc [63].

4.3 Data analysis

P-values <0.05 were considered statistically significant in papers I, II and IV. All analyses were done on version 23.0 and 24.0 of IBM SPSS Statistics for Windows (IBM, Armonk, NY, USA).

4.3.1 Paper I

In paper I differences in nominal variables, like gender, reported limiting factors to physical capacity such as poor fitness yes/no, or exercise past year ≥3 times/w, were analysed with Pearson’s ᵡ2 or Fisher’s exact test, when appropriate. The sig- nificance of differences between groups were either calculated by Mann-Whitney unpaired test or Student’s t-test when appropriate for continuous variables.

4.3.2 Paper II

In paper II Pearson’s ᵡ2 or Fisher’s exact test was used when analysing differ- ences in nominal variables, Mann-Whitney unpaired test was used for ordinal and non-normally distributed continuous variables whereas the Wilcoxon signed-ranks test was used when comparing observed values in the SSc-group with age- and gender-specific reference population values.

4.3.3 Paper III

In paper III content analysis as described by Graneheim and Lundman was used [107]. The analysis procedure followed a latent content analysis which made it possible to distil the content of the performed interviews into fewer content- related subcategories and categories. The categories were then grouped into over-arching themes. The latent content explores the interpreted meaning in the interview-material.

To get a rich variation of experiences of PA/exercise a purposeful sampling strategy was used [105]. This can help to ensure that a diversity of experiences is gathered in the sample of informants/patients with different degrees of lung involvement, age, gender and mix of lcSSc/dcSSc is included. A broad participation of differ- ent degrees of disease severity and other parameters increases the transferability (external validity) of the findings to other patient groups in other settings.

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The analysis started by familiarization through re-reading the transcribed interviews while listening to the tape recordings. This process was followed by condensation and coding of meaning units, i.e. constellations of words and sentences belonging to the same central meaning in relation to the aim of the study. In order to increase the credibility of the findings, investigator triangulation was performed with a senior researcher, an co-author of the manuscript, experienced in qualitative research [113].

Grouping and labelling of subcategories and categories were done in an iterative way by frequently returning to the transcripts as well as to the condensations and codes for additional reading to remain in line with the data. The codes were grouped into sub-categories which were then grouped into categories with similar content.

The categories were labelled to cover the content of the included subcategories.

To further increase the credibility of the analysis the preliminary categories were peer-reviewed in a multi-professional rheumatology healthcare research network group consisting of nurses, occupational therapists and physiotherapists. Main categories were developed by the Author and the senior researcher and discussed with another experienced researcher/co-author [107,114]. The main categories were further developed and sorted into overarching themes and then reviewed by the other researchers involved in the project [107] (Table 5).

Table 5. Steps and actions in the analysis in Paper III.

Steps Actions

1 Transcription and familiarization

Verbatim transcription, reading and re-reading to get at good grasp of each interview’s content

2 Condensation of meaning units

Condensation of interviews into meaning units

3 Coding

Coding of meaning units

4 Sorting, grouping, and labelling subcategories Sorting and grouping of codes into subcategories 5 Organising subcategories into categories

Subcategories combined into preliminary categories 6 Categories and Themes

Main categories were further merged into three overarching themes

References

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